Anti-TNFα domain antibody construct CEP-37247

Gay, Robert D.; Clarke, Adam W.; Elgundi, Zehra; Domagała, Teresa; Simpson, R. J.; Le, Nga B.; Doyle, Anthony; Jennings, Phil A.

doi:10.4161/mabs.2.6.13493

Cited by 27 publications

(6 citation statements)

References 35 publications

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“…There are documented examples of domain antibodies in development to address a number of autoimmune and inflammatory indications which would require repeat administrations of subcutaneously administered drug, for example TNF specific domain antibody constructs [33]. These molecules are currently undergoing evaluation in phase II clinical trials, demonstrating the utility of systemically administered domain antibodies in the development of novel therapeutics with antagonist activity.…”

Section: Discussionmentioning

confidence: 99%

Liver-Targeting of Interferon-Alpha with Tissue-Specific Domain Antibodies

et al. 2013

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Interferon alpha (IFNα) is used for the treatment of hepatitis C infection and whilst efficacious it is associated with multiple adverse events including reduced leukocyte, erythrocyte, and platelet counts, fatigue, and depression. These events are most likely caused by systemic exposure to interferon. We therefore hypothesise that targeting the therapeutic directly to the intended site of action in the liver would reduce exposure in blood and peripheral tissue and hence improve the safety and tolerability of IFNα therapy. We genetically fused IFN to a domain antibody (dAb) specific to a hepatocyte restricted antigen, asialoglycoprotein receptor (ASGPR). Our results show that the murine IFNα2 homolog (mIFNα2) fused to an ASGPR specific dAb, termed DOM26h-196-61, could be expressed in mammalian tissue culture systems and retains the desirable biophysical properties and activity of both fusion partners when measured in vitro. Furthermore a clear increase in in vivo targeting of the liver by mIFNα2-ASGPR dAb fusion protein, compared to that observed with either unfused mIFNα2 or mIFNα2 fused to an isotype control dAb VHD2 (which does not bind ASGPR) was demonstrated using microSPECT imaging. We suggest that these findings may be applicable in the development of a liver-targeted human IFN molecule with improved safety and patient compliance in comparison to the current standard of care, which could ultimately be used as a treatment for human hepatitis virus infections.

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Section: Discussionmentioning

confidence: 99%

Liver-Targeting of Interferon-Alpha with Tissue-Specific Domain Antibodies

et al. 2013

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“…Human IgG1 antibodies are frequently employed as human therapeutics, whereas human IgG2, IgG4 [1] and other antibody subclasses are less commonly used [1, 2, 3, 4, 5, 6, 7, 8, 9, 10]. While rodents are heavily utilized for pharmacokinetic (PK) assessment of antibodies, non-human primates, most commonly NHPs, are generally regarded as the better predictors of human pharmacokinetics for these molecules [11].…”

Section: Introductionmentioning

confidence: 99%

“…For example, the PK attributes of approved therapeutic antibodies in humans have a wide range with reported systemic half-lives from 79 to 648 hours and clearance rates of 0.141 to 1.017 ml/h/kg [12, 13]. The PK of conventional antibodies in NHPs also varies widely with serum half-lives ranging from 29 to 299 hours and clearance rates of 0.07 to 1.14 (ml/h/kg) [2, 3, 4, 5, 6, 7, 8].…”

Section: Introductionmentioning

confidence: 99%

Pharmacokinetic comparison of a diverse panel of non-targeting human antibodies as matched IgG1 and IgG2 isotypes in rodents and non-human primates

et al. 2019

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In this study we compared the pharmacokinetic profile of four unrelated antibodies, which do not bind to mammalian antigens, in IgG1 and IgG2 frameworks in both rats and non-human primates (NHP). This allowed for extensive cross comparison of the impact of antibody isotype, complementarity determining regions (CDR) and model species on pharmacokinetics without the confounding influence of antigen binding in the hosts. While antibody isotype had no significant impact on the pharmacokinetics, the CDRs do alter the profile, and there is an inverse correlation between the neonatal Fc receptor (FcRn) affinity and pharmacokinetic performance. Faster clearance rates were also associated with higher isoelectric points; however, although this panel of antibodies all possess basic isoelectric points, ranging from 8.44 to 9.18, they also have exceptional in vivo half-lives, averaging 369 hours, and low clearance rates, averaging 0.18 ml/h/kg in NHPs. This pattern of pharmacokinetic characteristics was conserved between rats and NHPs.

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“…Later, rare fully human rearranged V H and V L variable domains were discovered that were autonomously stable and monomeric and large phage display libraries were constructed by randomizing their complementarity-determining regions (CDRs), although it was clear from the mid-2000s that certain CDR sequences (potentially low in hydrophobic content and rich in negative charge) were better compatible with solubility and stability of these molecules ( 9 – 11 ). There are now many examples of fully human antibodies (primarily V H s) isolated from such libraries against a variety of targets, including α-amylase ( 12 ), β-galactosidase ( 13 , 14 ), Candida albicans MP65 and SAP-2 ( 15 ), carbonic anhydrase ( 12 ), CD154 ( 16 ), CD28 ( 17 ), CD40 ( 18 , 19 ), CD40L ( 20 ), Clostridium difficile toxin B ( 21 ), EGFR ( 22 ), glypican-2 ( 23 ), glypican-3 ( 24 ), human serum albumin (HSA) ( 25 – 27 ), lysozyme ( 28 – 30 ), maltose-binding protein ( 31 ), MDM4 ( 32 ), mesothelin ( 33 ), TNF-α ( 34 ), TNFR1 ( 35 ), and VEGF ( 22 ). These fully human V H /V L sdAbs exhibit a variety of antigen-binding modes and functional activities and several have entered clinical development, where they have been generally well-tolerated albeit unexpectedly immunogenic ( 36 , 37 ).…”

Section: Introductionmentioning

confidence: 99%

Stability-Diversity Tradeoffs Impose Fundamental Constraints on Selection of Synthetic Human VH/VL Single-Domain Antibodies from In Vitro Display Libraries

et al. 2017

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Human autonomous VH/VL single-domain antibodies (sdAbs) are attractive therapeutic molecules, but often suffer from suboptimal stability, solubility and affinity for cognate antigens. Most commonly, human sdAbs have been isolated from in vitro display libraries constructed via synthetic randomization of rearranged VH/VL domains. Here, we describe the design and characterization of three novel human VH/VL sdAb libraries through a process of: (i) exhaustive biophysical characterization of 20 potential VH/VL sdAb library scaffolds, including assessment of expression yield, aggregation resistance, thermostability and tolerance to complementarity-determining region (CDR) substitutions; (ii) in vitro randomization of the CDRs of three VH/VL sdAb scaffolds, with tailored amino acid representation designed to promote solubility and expressibility; and (iii) systematic benchmarking of the three VH/VL libraries by panning against five model antigens. We isolated ≥1 antigen-specific human sdAb against four of five targets (13 VHs and 7 VLs in total); these were predominantly monomeric, had antigen-binding affinities ranging from 5 nM to 12 µM (average: 2-3 µM), but had highly variable expression yields (range: 0.1-19 mg/L). Despite our efforts to identify the most stable VH/VL scaffolds, selection of antigen-specific binders from these libraries was unpredictable (overall success rate for all library-target screens: ~53%) with a high attrition rate of sdAbs exhibiting false positive binding by ELISA. By analyzing VH/VL sdAb library sequence composition following selection for monomeric antibody expression (binding to protein A/L followed by amplification in bacterial cells), we found that some VH/VL sdAbs had marked growth advantages over others, and that the amino acid composition of the CDRs of this set of sdAbs was dramatically restricted (bias toward Asp and His and away from aromatic and hydrophobic residues). Thus, CDR sequence clearly dramatically impacts the stability of human autonomous VH/VL immunoglobulin domain folds, and sequence-stability tradeoffs must be taken into account during the design of such libraries.Keywords: single-domain antibody, synthetic antibody, human Vh/Vl, phage display, protein engineering

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Anti-TNFα domain antibody construct CEP-37247

Cited by 27 publications

References 35 publications

Liver-Targeting of Interferon-Alpha with Tissue-Specific Domain Antibodies

Liver-Targeting of Interferon-Alpha with Tissue-Specific Domain Antibodies

Pharmacokinetic comparison of a diverse panel of non-targeting human antibodies as matched IgG1 and IgG2 isotypes in rodents and non-human primates

Stability-Diversity Tradeoffs Impose Fundamental Constraints on Selection of Synthetic Human VH/VL Single-Domain Antibodies from In Vitro Display Libraries

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